Human T cell leukemia virus type I (HTLV-I) is an RNA tumor virus identified as a causative agent of adult T cell leukemia and shown to be associated with several neurological and chronic disorders. An estimated 10 to 20 million people are infected by HTLV-I. Of these only a small percentage develop symptomatic disease, the majority of infections are silent. The mechanisms of the development and pathogenesis of HTLV-I associated diseases remain unknown. Studies of human viral isolates as well as evidence from animal models yield no data to correlate disease with genetic variation in the virus. This project is focused on understanding the pathogenic mechanisms of HTLV-I by means of studies on the interaction between HTLV-I viral products and various cellular molecules. These studies utilize virus that is known to cause disease in rabbits compared to those that cause asymptomatic infection. Investigations focus on two distinct HTLV-I infected rabbit cell lines: RH/K30 which mediates asymptomatic infection and RH/K34, which causes acute leukemia-like diseases. These lines have been characterized at the level of cell surface molecule, virus structure and molecular clones of the virus from each line has been obtained. Initial studies revealed only minor differences in the lines but more recent studies examining cellular signaling pathways that regulate cell proliferation, differentiation and programmed cell death show some differences. The status of tyrosine phosphorylation of several key proteins in RH/K30 and RH/K34 clearly indicate that there is constitutive tyrosine phosphorylation of certain proto-oncogene products only in the leukemogenic cell line RH/K34, but not in RH/K30. These results suggest that constitutive activation of certain signaling pathway may be associated with pathogenesis of HTLV-I infected cells. Other studies emphasize viral proteins that differ between the two strains; initial examinations of rex suggest that the protein from the pathogenic strain is deficient in ability to effect transport from the nucleus.